Table vii



United States Patent Ofi 3,126,321 Patented Mar. 24, 1964 ice 3,126,321SOFT GELATIN CAPSULES Walter M. Kurtz, Kalamazoo, Mich., assignor to TheUpjohn Company, Kalamazoo, Mich, a corporation of Delaware No Drawing.Filed Jan. 26, 1962, Ser. N 169,093 4 Claims. (Cl. 167-83) Thisinvention relates to gelatin capsules and more particularly to softgelatin capsules enclosing oleaginous compositions.

Soft gelatin capsules are known in the art. They are usually composed ofgelatin, water, and a plasticizer, such as glycerin, and can be formedinto various shapes and sizes.

The soft gelatin capsule of commerce is usually in the form of acontinuous outer shell of the composed gelatin enclosing a fluid orsemi-fluid fill. Dissolution of the shell or expression of the enclosedfill therefrom frees the fill for its intended use.

Since water has a marked aifinity for gelatin and can exert thereby adeleterious action on the capsule shell, fills of an oleaginous typehave been utilized to reduce the content of water in the fill. Even inthe case of oleaginous-type fills, small amounts of water have causeddefects in the yield and quality of capsules during preparation andstorage. Similarly, defects have been encoun tered in capsules enclosingotherwise acceptable and useful oleaginous fills, for example, thoseincluding salts of strong acids and bases, such as sodium chloride;hygroscopic compounds, such as chloral hydrate; hydrochlorides, such as(o-methoxy-a-methylphenyl)-hydrazine hydrochloride; water solublecompounds, such as choline chloride; volatile solvents, such as alcohol;and non-volatile solvents, such as glycerin. The said defects greatlyreduce the yield of quality-controlled capsules and impair the storagestability of the capsules; for example, through leaking, indenting, andshrinking of the capsules and the existence of excessively soft capsulesand those with soft spots. Apparently, substances, such as the salts,hygroscopic compounds, hydrochlorides, water-soluble compounds, volatileand nonvolatile solvents, per so, have a deleterious action on thegelatin shell of the capsules, especially in the presence of water. Thedeleterious action of like substances is determined readily by a testrun such as demonstrated in Tables I through VI.

It has now been discovered that, according to the present invention,oleaginous vehicles can be successfully filled into soft gelatincapsules by the use in the fill of an ingestible cellulosic compound,such as purified cellulose. The operability of an ingestible cellulosiccompound is determined readily by a test run such as demonstrated inExample 1. As is known in the art, the oleaginous vehicles comprisefixed oils, such as corn oil and cottonseed oil; oily esters, such asisopropyl myristate; and the like. Oil-dispersible components, such asaluminum monostean ate, white wax, and hydrogenated oils, can beincorporated into the oleaginous vehicles. For oral administration thevehicles and any added components must be ingestible. The invention isespecially advantageous in the case of an oleaginous fill including aningredient having a deleterious action on the gelatin, and especially aningredient having such action in the presence of Water.

The fill should be fluid enough for handling in the practical methodsused in encapsulating flowing vehicles and compositions. An amount ofthe cellulosic compound up to about 20% by weight of the fill isfeasible, and in some compositions higher amounts can be used. Toprovide best results any water included within the fill should usuallybe no more than about twice the amount of the cellulosic compound.

The mechanism of action of the said cellulosic compound in preventingthe defects in yield and storage of the capsules is not completelyunderstood. However, experimental data show that unexpectedly highyields of quality-controlled capsules are obtained from the compositionsand process of the instant invention.

The heretofore unsolved problems are illustrated in the followingtables, the percents of capsules accepted being those obtained afterwashing, drying and quality inspecting the capsules prepared by theknown methods, the percents of ingredients being by weight.

TABLE I Results of Quality Control Inspection. Percent of CapsulesAccepted oleaginous Vehicle 67.79, Balance- Corn Oil, Water, 15%

collapsed shells.

TABLE II Corn Oil, 84%; Compound A 16% 27.08, Balance- Leakers.

TABLE III 0.00, All leakers.

82.37, Balanceleakers.

0.00, All lcakers.

TABLE IV Corn Oil, alcohol, 10% 37.50, Balanceakers.

TABLE V Corn Oil, 90%; glycerol, 10%. 0.00, All spotted. Corn 011, 88%;glycerol, 12% 0.00, All spotted.

TABLE VI 90.22, Balance- Corn Oil, 93%; chloral hydrate, 7%

leakers.

Compound A is (o-methoxy-a-methylphenyl) hydrazine hydro chloride.

TABLE VII Results of Quality Oleaginous Vehicle Control Inspection,

Percent of Gapsules Accepted Corn Oil, 83%; purified cellulose, 6%;water, 117... 92.07.

TABLE VIII Coin gil, 89.1%; purified cellulose, 2%; Compound 99.25.

x CtXnSO9i l 86.1%; purified cellulose, 5%; Compound 99.76. Corii 91.1%;purified cellulose, Compound 99.08. Isopro pyi myristate, 84%; purifiedcellulose, 10%; 99.84.

Compound A, 16%. Corn Oil, 74%; crystalline cellulose, 10%; Com- 9936.

pound A, 16

TABLE IX Corn Oil, 83%; purified cellulose, 10%; NaGl, 7%... 96.60.Peamt Oil gel, 78%; purified cellulose, NaOl, 96.47.

1 Coru Oil, 77%; purified cellulose, 10%; NaCl, 3%; 97.30.

water, 10%.

TABLE X Corn Oil, 80%; purified cellulose, 10%; alcohol, 10%. 99.28.

TABLE XI (Joan Oil, 80%; purified cellulose, 10%; glycerin, 97.08, Nosoil;

1 spots. Corn Oil, 76%; purified cellulose, 12%; glycerin, 99.44, Nospotting 12%. or shrinking.

TABLE XII Corn Oil, 74%; purified cellulose, 10%; chloral 07.84.

hydrate, 10%. Corn Oil, 81%; purified cellulose, 10%; chloral 95.67.

hydrate, 7%; water, 2%.

Compound A is (o-metlioxy-a-methylphenyl) hydrazine hydrochloride.

The above data show the superiority, greatly improved yields andacceptable physical characteristics of the capsules and methods of theinstant invention.

In the manner and process of making the invention, an oleaginouscomposition is prepared by mixing and blending the components thereofinto a homogeneous whole, using the known techniques for preparingoleaginous vehicles for encapsulation into soft gelatin capsules. Theorder of addition of components to the oleaginous vehicle is notcritical. The oleaginous fill is thereafter encapsulated by the knowntechniques.

The invention is used to provide increased yields of accepted softgelatin capsules, especially ingestible soft gelatin capsules.

The following examples set forth the best mode contemplated by theinventor of carrying out his invention.

EXAMPLE 1 Capsules Enclosing an Oleaginous Composition Comprising Water400 cms. of an oleaginous composition is prepared from the followingingredients:

Grams Purified water, U.S.P 60 Corn oil 300 Purified cellulose, powdered40 4i The composition is encapsulated into 2.65 minim soft gelatincapsules by the known techniques. 99.6 percent of the capsules are foundacceptable by the quality control inspectors.

EXAMPLE 2 Capsules Enclosing an Oleaginous Composition Comprising aHydrochloride 300 gms. of an oleaginous composition is prepared from thefollowing ingredients:

Grams (o Methoxy-a-methylphenyl)hydrazine hydrochloride 48 Isopropylmyristate 222 Purified cellulose 30 EXAMPLE 3 Capsules Enclosing anOleaginous Composition Comprising a Volatile Solvent 400 gms. of anoleaginous composition is prepared from the following ingredients:

Grams Alcohol, U.S.P 40 Corn oil 320 Purified cellulose 40 CapsulesEnclosing an Oleaginous Composition Comprising a Nonvolatile Solvent 400gms. of an oleaginous composition is prepared from the followingingredients:

Grams Glycerin, U.S.P 40 Cottonseed oil 320 Purified cellulose 40 300gms. of an oleaginous composition is prepared from the followingingredients:

Grams Chloral hydrate 48 Corn oil 222 Purified cellulose 30 The corn oilis stirred vigorously, and the chloral hydrate is added gradually toform a good solution. Thereafter the purified cellulose is added duringcontinuous stirring to form a homogeneous mixture.

The composition is encapsulated into 2.65 minim soft gelatin capsules bythe known techniques. 97.84 percent of the capsules are found acceptableby the quality control inspectors.

EXAMPLE 6 Capsules Enclosing an Oleaginous Composition Comprising a Saltand Water 400 gms. of an oleaginous composition is prepared from thefollowing ingredients:

Grams Sodium chloride, powder l2 Purified water, U.S.P 40 Corn oil 308Purified cellulose 40 of the capsules are found acceptable by thequality control inspectors.

What is claimed is:

1. A filled soft gelatin capsule wherein the fill comprises a fluidoleaginous vehicle and powdered ingestible cellulose.

2. A filled soft gelatin capsule wherein the fill comprises a fluidoleaginous vehicle, powdered ingestible cellulose, and an ingredienthaving a deleterious action on gelatin.

3. A filled soft gelatin capsule wherein the fill comprises a fluidoleaginous vehicle and up to about 20% by weight of the fill of powderedingestible cellulose.

4. A filled soft gelatin capsule wherein the fill comprises a fiuidoleaginous vehicle, up to about 20% by weight of the fill of powderedingestible cellulose and an ingredient having a deleterious action ongelatin.

References Cited in the file of this patent UNITED STATES PATENTS MurphyOct. 24, 1950 2,581,038 Middendorf Jan. 1, 1952 2,667,268 Grifiin Jan.26, 1954 2,780,355 Palermo et al Feb. 5, 1957 UNITED STATES PATENTOFFICE CERTIFICATE OF CORRECTION Patent No. 3,126,321 March 24', 1964Walter M Kurtz It is hereby certified that error appears in the abovenumbered pat- I ent req'iiring correction and that the said LettersPatent should read as corrected below.

Column 3, TABLE VIII, line 7 thereof, for "84%" read 74% same column 3,line 64, for "400 cms, read 400 Gms.

Signed and sealed this 28th day of July 1964a (SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents ESTON G. JOHNSON AttestingOfficer

1. A FILLED SOFT GELATIN CAPSULE WHEREIN THE FILL COMPRISES A FLUIDOLEAGINOUS VEHICLE AND POWDERED INGESTIBLE CELLULOSE.